WO1990008760A1

WO1990008760A1 - Use of hexatriene derivatives for the manufacture of preparations for treating acne, psoriasis and light-induced damage to the skin

Info

Publication number: WO1990008760A1
Application number: PCT/EP1989/000104
Authority: WO
Inventors: Hans-Heiner WÜST; Fritz-Frieder Frickel; Joachim Paust; Klaus Schmieder; Axel NÜRRENBACH
Original assignee: Basf Aktiengesellschaft
Priority date: 1989-02-02
Filing date: 1989-02-02
Publication date: 1990-08-09
Also published as: EP0413692A1; EP0413692B1; JPH04501847A

Abstract

Use of hexatriene derivatives of formula (I), where R1 has the meaning given in the description, for the manufacture of pharmaceutical and cosmetic preparations for treating acne, psoriasis and other dermatological diseases accompanied by pathological cornification and for treating iatrogenic skin damage or skin damage caused by the action of UV light, eczema, warts, vitiligo, dry eyes and other corneopathies, as well as precanceroses and tumours, rheumatic and arthritic diseases.

Description

Use of hexatriene derivatives for the production of agents against acne, psoriasis and light damage to the skin

description

The invention relates to the use of hexatriene derivatives in the manufacture of therapeutic and cosmetic agents for skin care.

It is known that polyene compounds such as retinol or retinoic acid, and also those compounds in which one or more aromatic rings are incorporated in the polyene structure, have pharmacological effects in the topical and systemic therapy of neoplasms and dermatoses, e.g. Acne or psoriasis, (R.C. Moon and L.M. Hri in "The Retinoids" (Ed. M.B. Sporn, A.B. Roberts and D.S. Goodman), Vol. 2, p 327 ff,

Academic Press, Inc. 1984; G.L. Peck, ibid. Vol. 2, p. 391 ff). However, they also have undesirable side effects.

From M.I. Dawson et al., J. Meth. Chem. 27 (1984), 1516 to 1531 it is known that 4 - [(E) -3-methyl-6- (2,6,6-trimethylcyclohexen-1-yl) 1 , 3,5-hexatrienyl] benzoic acid in an in vivo and in vitro test model shows anticancerogenic effects.

The invention was based on the object agents for the treatment of acne and psoriasis and other dermatological diseases associated with pathological cornification with a more favorable spectrum of action and

Develop agents for general skin care, in particular for the prevention and healing of sun damage to the skin.

It has now been found that substituted hexatriene derivatives of the formula I

in which R ^{1 is} a methyl group, a nitrile or C ₂ - to cio-ketal group of the formula

where R ', R "and R'" represent alkyl groups with 1 to 9 carbon atoms, the sum of the carbon atoms of R ', R "and R"' is 2 to 10 and R 'also May be hydrogen, an oxazolinyl or tetrazolyl radical, or the radicals -CH ₂ OR ² , -CH ₂ NR ³ R ⁴ or -COR ⁵ , in which

R ² is a hydrogen atom, a C ₁ - ₂₀ alkanoyl or optionally substituted benzoyl group,

R ³ and R ^{4 are} hydrogen atoms, C _{_1-4} alkyl, C _{_1-6} alkanoyl or an optionally substituted benzoyl group or together with the nitrogen atom to which they are bonded, a heterocyclic radical, and

R ⁵ is a hydrogen atom, a C ₁ - ₄ alkyl group, a halogen atom or the radicals -0R6 or -NR R 8, wherein R ⁶ represents a hydrogen atom, an optionally substituted by hydroxyl Ci-C _ß alkyl group or an optionally substituted aryl - Or optionally substituted aralkyl group in the aryl part, and

R ⁷ and R ^{8 represent} hydrogen atoms, optionally by hydroxyl groups

substituted C ₁ -C ₆ alkyl groups or optionally substituted aryl or optionally substituted aralkyl groups in the aryl part or together with the nitrogen atom to which they are attached represent a heterocyclic radical, and optionally their physiologically tolerable salts have an improved action against acne and psoriasis and other dermatological diseases associated with pathological cornification, especially with regard to the therapeutic range, and are suitable for curing UV light damage to the skin.

R ¹ is preferably a COOH group.

The preferred aryl group for R ⁶ , R ⁷ and R ^{8 is} the phenyl group, which can be substituted by a methyl, methoxy or nitro group; as the aralkyl group for R ⁶ , R ⁷ and R ⁸ the benzyl group is preferred, which may be substituted in the aryl part with a methyl or methoxy group or with halogen. Substituents of the benzoyl group can be, for example, the methyl or methoxy group or halogen. The heterocyclic radicals for R ³ and R ⁴ or R ⁷ and R ⁸ are preferably the pyrrolidino, piperidino or morpholino radical. Halogen atoms for R ^{5 are} preferably fluorine and chlorine.

The IE connections are preferred over the 1Z connections. Typical examples of compounds to be used according to the invention are:

(all-E) -1- (4-carboxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-carbomethoxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-carbethoxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-carbopropyloxphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-carbobutoxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-cyanophenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-fluorocarbonylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-chlorocarbonylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-carbamoylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -l, 3,5-hexatriene

(all-E) -1- [4- (butylcarbamoyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (diethylcarbamoyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (2-Hydroxyethylcarbamoyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (phenylcarbamoyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1¬

-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (benzylcarbamoyl) phenyl)] - 4-methyl-6- (2,6,6-trimethyl-1¬

-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- (4-formylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen¬

-1-yl) -1,3,5-hexatriene

(all-E) -l- (4-acetylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -l, 3,5-hexatriene

(all-E) -1- [4- (hydroxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1¬

-cyclohexen-l-yl) -l, 3,5-hexatriene

(all-E) -1- [4- (methoxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1¬

-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (phenoxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene (all-E) -1- [4- (benzyloxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (formyloxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (acetoxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (propionyloxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1¬

-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (hexadecanoyloxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (aminomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclo¬

-hexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (N, N-diethylaminomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl¬

-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (pyrrolidinomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl¬

-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (piperidinomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl¬

-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (N-formylaminomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (N-acetylaminomethyl) phenyl] -2,6,6-trimethyl-1-cyclohexene-1¬

-yl) -1,3,5-hexatriene

(all-E) -1- [4- (N-benzoylaminomethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

(all-E) -1- [4- (dioxolan-2-yl) phenyl] -4-methyl-6- (2,6, θ-trimethyl-1-cyclohexen-1-yl) -1,3,5 -hexatriene

(all-E) -1- [4- (oxazolin-2-yl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-y1) -1,3,5 -hexatriene

(all-E) -1- [4- (tetrazol-5-yl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5 -hexatriene

(1Z, 3E, 5E) -1- (4-carboxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1, 3, 5-hexatriene

(1Z, 3E, 5E) -1- (4-carbomethoxyphenyl) -4-methyl-6- (2, 6, 6-trimethyl-1-cyclohexen-1-yl) -1, 3, 5-hexatriene

(1Z, 3E, 5E) -1- (4-carbethoxyphenyl) -4-methyl-6- (2, 6, 6-trimethyl-1-cyclohexen-1-yl) -1, 3, 5-hexatriene

(lZ, 3E, 5E) -1- (4-cyanophenyl) -4-methyl-6- (2,6, 6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene The compounds to be used according to the invention can be prepared by using a phosphonium salt of the formula II

where X ^{Θ is} anions such as chloride, bromide or preferably hydrogen sulfate, with an aromatic aldehyde of the formula III

wherein R ⁹ is methyl or nitrile group or a group -COOR ¹⁰ and R ¹⁰ is a hydrogen atom or a C ₁ - ₃ alkyl group, in a

Wittig reaction implemented. It is advisable to work in one

Solvents in the presence of the basic compounds customary for Wittig reactions.

The Wittig reaction proceeds at a temperature of up to 100 ° C, advantageously at 20 to 50 ° C. The reaction can be carried out at atmospheric pressure or in a closed vessel under elevated pressure, if appropriate with heating to the specified temperature range.

This reaction can be carried out in the presence of a diluent or solvent, for example a lower saturated dialkyl ether,

Dialkyl glycol ether or cyclic ether, such as diethyl ether,

Ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon such as hexane, heptane or isooctane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkyl formamide such as dimethyl or diethyl formamide, or in mixtures of the solvents mentioned. Cyclic ethers such as dioxane or tetrahydrofuran and, in particular, dimethylformamide or mixtures thereof are preferably used, the reaction generally being carried out in a

Temperature expires up to 30 ° C.

The reactions are carried out in the presence of a deprotonating agent for the phosphonium salt II. Alkali metal hydrides and Alkali metal amides, especially sodium and potassium, the

Sodium or potassium salts of dimethyl sulfoxide, alkyl lithium compounds such as n-butyllithium or alkali metal alcoholate, preferably sodium methoxide and sodium ethanolate.

The compounds to be used according to the invention can also be obtained by the Wittig-Horner variant, the aldehyde IV

with a phosphonate of formula V

in which R ^{1 has} the meaning given above and R ¹⁰ for one

C _{_1-4} alkyl radical, is reacted. These reactions are similar to the Wittig reactions described above in the presence of a suitable deprotonating agent.

The Wittig or Wittig-Horner reaction usually gives mixtures of the sterically isomeric (E / Z) -01efins.

E / Z isomer mixtures with a predominant Z component are rearranged under the influence of light on the olefinic double bond to mixtures with a higher proportion of the (E) isomers. Pure (E) compounds of the formula (I), preferably by crystallization or a chromatographic method such as column or preparative HPL chromatography, are advantageously obtained from the (E / Z) isomers with a now more favorable (E) content.

The photoisomerization is preferably carried out in solution. Suitable solvents are polar protic or aprotic solvents, e.g. Methanol, ethanol, ethyl acetate, tetrahydrofuran, acetone. The concentration of the irradiated solution is 0.1 to 50, preferably 1 to 15 percent by weight.

You can irradiate in the presence of sensitizers such as acetophenone, 4-methoxyacetophenone, propiophenone, benzene, acetone, benzophenone, benzil, Michler's ketone. Acetone is particularly preferred here. Artificial emitters whose emission is at least partially in the range from 200 to 600 nm, preferably in the range from 300 to 400 nm, can be used as the light source for carrying out the aforementioned photo reaction. Mercury vapor, fluorine, xenon or tungsten lamps, fluorescent tubes or carbon arc lamps are advantageous.

The irradiation temperature depends on the type of solvent used. The range from +10 to + 30 ° C. is particularly preferred. The radiant heat can be removed by lamp cooling and / or cooling of the reaction mixture, it being possible to use distilled water or filtering solutions provided with additives in a known manner in the lamp cooling circuit.

If desired, the benzoic acid esters of the general formula I are converted into the free carboxylic acids and their physiologically compatible ones

Salts, converted by ester saponification. Conversely, the free acid can of course be esterified in a known manner.

The saponification / esterification is expediently carried out in the presence of a diluent or solvent, for example a dialkyl glycol ether or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or in a lower aliphatic alcohol , such as methanol, ethanol, propanol or isopropanol, optionally in

In the presence of water or in mixtures of the solvents mentioned with water.

Preferred solvents are aqueous mixtures of ethanol and methanol, the reaction being carried out at the boiling point of the reaction mixture.

The saponification preferably takes place in the presence of alkali, such as

Alkali metal hydroxides, alkali metal carbonates and hydrogen carbonates, especially of sodium and potassium, organic tertiary bases such as pyridine or lower trialkylamines such as trimethyl or triethylamine in mixtures with water. The base used in relation to the ester is used in a stoichiometric amount or in a slight excess. Sodium or potassium hydroxide is preferably used. The amides to be used according to the invention can be prepared in a manner known per se by first converting the corresponding benzoic acids into carbonylactic derivatives, for example into the acid halides, azides, imidazolides or anhydrides, the O-acyl-N, N'-dicyclohexylisoureas or p-nitrophenyl esters, and these are treated with amines HNR ⁷ R ⁸ . In the case of particularly reactive amines, especially ammonia, the direct amidolysis of esters (with the radical -OR ⁶ ) is preferred.

A halide of a carboxylic acid, preferably the acid chloride, can be reacted with 2-aminoethanol and then cyclized into one

Oxazoline derivative of formula I are transferred.

A carboxylic acid, a carboxylic acid ester or a carboxylic acid amide

Formula I can be reduced to the corresponding alcohols or amines in a manner known per se. The reduction is advantageously carried out with the aid of a metal hydride or alkali metal hydride in the presence of a suitable solvent. Complex metal hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride are preferably used as metal hydrides. As a solvent when working with

Lithium aluminum hydride ethers used, such as diethyl ether, dioxane or tetrahydrofuran. If the reduction is carried out with diisobutyl aluminum hydride or an alkoxysodium aluminum hydride, the use of hydrocarbons such as hexane or toluene is preferred.

An amine or an alcohol of the formula I can be prepared in a manner known per se with an alkanoyl halide or anhydride, an aralkyl halide or anhydride or an aroyl or heteroaroyl halide or anhydride, advantageously in an inert diluent or solvent, for example a lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide such as dimethylformamide or diethylformamide or with excess acylating agent as a diluent or solvent in the amides and esters according to the invention. The reactions are preferably carried out in the presence of a base as an acid-binding agent in a temperature range between -20 ° C. and the boiling point of the reaction mixture. Suitable bases are alkali metal carbonates, hydrogen carbonates, hydroxides or alcoholates, especially of sodium and potassium, basic oxides such as aluminum oxide or calcium oxide, organic tertiary bases such as pyridine, or lower trialkylamines such as trimethyl or triethylamine. The bases in relation to the alkylating agent used can be used in a catalytic amount or in a stoichiometric amount or in a slight excess. An alcohol of formula I can with alkyl halides R2-J, R2-Br or R2-C1 in the presence of alkali metal hydrides, preferably sodium hydride or in the presence of alkyl lithium compounds, preferably n-butyllithium, in an organic solvent such as tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, methyl tert-butyl ether or, if sodium hydride is used, also in dimethylformamide in a temperature range between -10 ° C. and 40 ° C. to give an ether of the formula I.

An alcohol of formula I can with suitable oxidizing agents,

preferably manganese (IV) oxide, optionally oxidized to an aldehyde of the formula I on an inorganic support material such as silica gel or aluminum oxide. It is advantageous to work in an inert organic solvent, for example a hydrocarbon such as hexane or in an ether such as tetrahydrofuran or in mixtures of the solvents and diluents mentioned in the temperature range between -10 ° C. and 30 ° C. The reaction time required essentially depends on the oxidation activity of the manganese (IV) oxide used. An aldehyde of the formula I can also be obtained by reducing the corresponding nitrile of the formula I with diisobutylaluminum hydride in a solvent, preferably in toluene, hexane, tetrahydrofuran or mixtures of these solvents in a temperature range between -40 ° C. and room temperature.

A nitrile of the formula I can be saponified to the corresponding carboxylic acid in a manner known per se with acid or advantageous base catalysis. Preferred bases are alkali metal hydroxides, particularly

Potassium hydroxide, which is used in excess. As a rule, water-miscible alcohols such as e.g. Methanol, ethanol, isopropanol or n-butanol are used. The reaction is usually carried out at the boiling point of the reaction mixture.

From the nitriles of formula I by addition of an azide, e.g.

an alkali metal azide, preferably sodium azide, in the presence of

Aluminum chloride or ammonium chloride, the corresponding tetrazoles of the formula I can be obtained. Cyclic ethers such as dioxane or tetrahydrofuran, and in particular dimethylformamide or mixtures thereof, are preferably used as solvents, the reaction generally taking place at a temperature of 60 to 100.degree. Some of the compounds to be used according to the invention have an acidic hydrogen atom and can therefore be converted with bases in a customary manner into a physiologically compatible, readily water-soluble salt. Suitable salts are, for example, ammonium, alkali metal, in particular sodium, potassium and lithium, alkaline earth metal salts, in particular calcium or magnesium, and salts with suitable organic bases, such as with lower alkylamines, for example methylamine, ethylamine or cyclohexylamine, or with substituted lower alkylamines , in particular

hydroxy-substituted alkylamines, such as diethanolamine, triethanolamine or tris (hydroxymethyl) aminomethane, and with piperidine or morpholine.

If appropriate, the amines of the formula (I) to be used according to the invention are converted into the acid addition salt of a physiologically tolerated acid by a known procedure. As usual

Physiologically compatible organic or inorganic acids are suitable, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, and organic acids are, for example, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid or benzoic acid. More can from

Advances in Drug Research Volume 10, pages 224 to 225,

Birkhäuser-Verlag, Basel and Stuttgart, 1966.

The compounds to be used according to the invention and their physiologically tolerable salts can, due to their pharmacological properties in topical and systemic prophylaxis and therapy of acne, psoriasis and other dermatological diseases associated with pathological cornification, in particular ichthyosis, Dariersche

Disease, lichen, leukoplakia, but also against eczema, vitiligo and warts, furthermore against dry eyes and other corneal pathies,

Precancerous and tumors, rheumatic and arthritic diseases and especially iatrogenic or damage to the skin caused by sunlight (UV radiation) (actinic keratosis).

The pharmacological effects can be demonstrated, for example, in the following test models:

The dermatological activity, e.g. for the treatment of acne, can include by the comedolytic activity and the ability to demonstrate the number of cysts in the Rhino mouse model

reduce (LH Kligman et al., The Journal of Investigative Dermatology 73, 354-358 (1978)). A further measure of the dermatological activity can be the reduction of the sebaceous glands and the associated reduced production of taig on the side organ of the hamster. This methodology has been developed by EC Gomez in J.Am. Dermatol. 6, 746-750 (1982). Furthermore, the reversion of skin damage caused by UV light that can be achieved by the compounds according to the invention can be determined in animal models. This methodology is also from LH

Kligman et al. described in Connect. Tissue Res. 12, 139-150 (1984) and in the Journal of the American Academy of Dermatology 15, 779-785 (1986).

Accordingly, the subject of the invention are therapeutic and

cosmetic agents for topical and systemic use, which contain a compound of formula (I) in addition to conventional carriers or diluents as an active ingredient, and the use of a compound of formula (I) for the preparation of such a medicament or cosmetic for acne, psoriasis and others with pathological Cornification

associated dermatological diseases as well as against iatrogenic or skin damage caused by exposure to UV light, against eczema, warts, vitiligo, dry eyes and other corneopathies, also against

Precancerous and tumors as well as rheumatic and arthritic

Diseases.

The therapeutic and cosmetic agents or preparations are produced using the customary liquid or solid carriers or diluents and the pharmaceutical-technical or cosmetic auxiliaries used in the customary manner, in accordance with the desired type of application and with a suitable one for use

Dosage, in the usual way, for example by mixing the

Active ingredient with the solid or liquid carriers and auxiliaries which are conventional in such preparations.

Accordingly, the agents can be administered orally, parenterally or topically. Such preparations are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusion or injection solutions, and pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays. Topical application is preferred. When used locally, the therapeutic and cosmetic agents can contain the compounds to be used according to the invention in 0.001 to 1% strength

Concentration, preferably in 0.01 to 0.1% concentration and, in the case of systemic use, preferably in a single dose of 0.1 to 50 mg, and are administered daily in one or more doses depending on the type and severity of the diseases. commonly used pharmaceutical-technical and cosmetic

Auxiliaries are, for example, alcohols such as isopropanol, oxyethylated castor oil or oxyethylated hydrogenated for local use Castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, petroleum jelly, wool fat, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol, for systemic use milk sugar, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone. The

An antioxidant, for example tocopherol and butylated hydroxyanisole or butylated hydroxytoluene or flavor-improving additives, stabilizers, emulsifiers, lubricants, etc. can optionally be added to preparations. The prerequisite is that all substances used in the manufacture of pharmaceutical and cosmetic preparations are toxicologically harmless and that they are used

Active ingredients are compatible.

Preparation of the compounds to be used according to the invention: Example 1

To a solution of 116.8 g (0.2 mol) of ß-lonylidenethyltriphenylphosphonium hydrogen sulfate and 32.7 g (0.25 mol) of p-cyanobenzaldehyde in 0.5 1 of methanol was at 0 to 5 ° C within 15 min Solution of 7.8 g (0.34 mol) of sodium in 62 ml of methanol was added dropwise. They were left for 18 hours

Stir room temperature, then mixed with 100 ml of water and filtered off insoluble components. The filtrate was five times with 300 ml

Heptane / ether (5: 1) extracted. After drying (Na ₂ SO ₄ ) and concentration of the organic phase, 521 g of solid remained. This was from 200 ml of methanol + 100 ml of ethanol and then again from 300 ml of heptane

recrystallized. This gave 15.1 g of crystals (E / Z = 3: 1).

By recrystallization from 75 ml of heptane, 10.2 g (16%) of the title compound were obtained isomerically pure, mp. 120 to 121 ° C.

Example 2

(all-E) - and (lZ, 3E, 5E) -1- (4-carbethoxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-l-yl) -1,3 , 5-hexatriene

To a solution of 95.5 g (0.17 mol)

β-Ionylidenethyltriphenylphosphonium hydrogen sulfate and 37.4 g (0.21 mol) of ethyl p-formylbenzoate in 400 ml of absolute ethanol was at 5 to

10 ° C., a solution of 6.3 g (0.275 mol) of sodium in 135 ml of absolute ethanol was added dropwise within 25 min. The mixture was allowed to stir at room temperature for 18 h and then the reaction mixture was concentrated to a quarter of its volume.

The residue was mixed with 250 ml of heptane and mixed thoroughly.

Then the heptane phase was decanted off and the entire process was repeated two more times. The combined heptane phases were three times with each 250 ml of methanol / water (3: 2) washed, dried (Na ₂ SO ₄ ) and concentrated. The residue was separated by means of preparative HPLC (silica gel 60, heptane + 1% ethyl acetate). The first fraction contained 12.8 g (21%)

1Z isomer of the title compound as an oil. The second fraction consisted of 13.8 g of crystals, which was stirred with 10 ml of ethanol and suction filtered. 3.4 g (11%) of all-E isomer of the title compound, mp. 140 to 141 ° C., were thus obtained.

Example 3

(all-E) -1- (4-carboxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene a) 4 g ( 12.6 mmol)

(all-E) -1- (4-cyanophenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene from Example 1 were described in 60 ml of ethanol + 40 ml of 10 N sodium hydroxide solution heated under reflux for 2 h. It was poured onto water and acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed neutral with water, washed with a little methanol and dried. 4 g (94%) of slightly contaminated product with a melting point of 215 ° C. were obtained.

For further purification, the product was recrystallized once from toluene / heptane and a second time from isopropanol. 2.6 g (61%) of pure title compound were obtained, mp. 218 ° C. b) 2.9 g (8 mmol)

(all-E) -1- (4-carbethoxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene from Example 2 became 2 , 5 h in a solution of 1.1 g of potassium hydroxide (85%) in 35 ml of ethanol

Reflux heated. After cooling, the mixture was poured onto 0.5 l of water and 50 ml of ethanol, acidified, stirred for a few minutes and the precipitate formed was filtered off with suction, which was washed thoroughly with water and several times with a little ethanol. After drying, 2.6 g (97%) of the title compound remained as yellow crystals, mp. 219 to 220 ° C.

Example 4

(1Z, 3E, 5E) -1- (4-carboxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1yl) -1,3,5-hexatriene To a solution from 112 , 4 g (0.2 mol) of β-ionylidene ethyl triphenylphosphonium hydrogen sulfate and 37.5 g (0.25 mol) of p-carboxybenzaldehyde in 500 ml of absolute ethanol, a solution of 15.6 g (0 , 68 mol) sodium in 400 ml of absolute ethanol was added dropwise. The mixture was left to stir at room temperature for 18 h, then poured onto 1 l of water and acidified and extracted 3 mol with 250 ml ether each. The greasy residue remaining after drying (Na ₂ SO ₄ ) and concentrating the combined ether phases was triturated with 400 ml of ethanol. The crystals were filtered off and washed several times with a total of 200 ml of acetone. Recrystallization from ethyl acetate gave 18.4 g (27%) of the title compound, melting point 179 ° C.

Example 5

(all-E) -1- [4- (tetrasol-5-yl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5 -hexatriene

6.7 g (0.05 mol) of aluminum chloride were carefully added in portions to a suspension of 13 g (0.2 mol) of sodium azide in 100 ml of tetrahydrofuran at 0 ° C. The mixture was heated under reflux for 45 min, and 3.2 g (0.01 mol) of (all-E) -1- (4-cyanophenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexene were added -1-yl) -1,3,5-hexatriene from Example 1 and heated under reflux for a further 18 h. The reaction mixture was then poured into 0.7 l of water, 200 ml of ethanol were added and the mixture was acidified. After a long time

Stirring at room temperature formed a solid which was suction filtered and washed with ethanol / heptane (1: 1). After drying, 2.6 g (72%) of the title compound were obtained, mp. 195 to 196 ° C.

Example 6

(all-E) -1- (4-formylphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene

To a solution of 19 g (0.06 mol) (all-E) -1- (4-cyanophenyl) -4-methyl- -6- (2,6,6-trimethyl-1-cyclohexen-l-yl) -1,3,5-hexatriene from Example 1 in a mixture of 250 ml of absolute ether and 50 ml of absolute tetrahydrofuran, a solution of 0.12 mol of diisobutylaluminum hydride in 100 ml of toluene was quickly added dropwise with gentle cooling at 5 to 10 ° C. The mixture was left to stir at room temperature for 2 h and then hydrolyzed carefully with water and saturated tartaric acid solution. The mixture was extracted 7 times with 200 ml of ether each time, the combined ether phases were washed once with water, dried (Na ₂ SO ₄ ) and concentrated. The residue (20 g dark brown oil) was purified by column chromatography (silica gel 60, 230 to 400 mesh, 180 g; heptane with increasing proportions of toluene). This gave 11.1 g (58%) of the title compound, mp. 62 to 63 ° C. At game 7

(all-E) -1- [4- (hydroxymethyl) phenyl] -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene 9, 6 g (0.03 mol) of the aldehyde described in Example 6 above were dissolved in 300 ml of isopropanol and a total of 2.3 g (0.06 mol) of sodium borohydride were added in portions at room temperature. The mixture was left to stir at room temperature for 2 h, then poured onto 0.6 l of water and extracted 3 times with 150 ml of ether each time. The combined ether phases were washed once with saturated sodium chloride solution, dried (Na ₂ O ₄ ) and concentrated. The residue (8.7 g of oil) was purified by column chromatography (silica gel 60, 230 to 400 mesh; heptane with increasing proportions of ethyl acetate). After concentration, the eluate was crystallized by trituration. The solid (4.4 g) was thoroughly stirred in 15 ml of heptane, suction filtered and dried. 3.0 g (30%) of the title compound were obtained; 69 to 70 ° C.

Claims

1. Use of hexatriene derivatives of the formula I.

in which R ¹ denotes a methyl group, a nitrile or C ₂ - to C ₁₀ -ketal group, an oxazolinyl or tetrazolyl radical or the radicals -CH ₂ OR ² , -CH ₂ NR ³ R ⁴ or -COR ⁵ , in which

R ³ and R ^{4 are} hydrogen atoms, C _{_1-4} alkyl, C _{_1-6} alkanoyl or an optionally substituted benzoyl group or together with the nitrogen atom to which they are attached form a heterocyclisehen radical, and

R ⁵ is a hydrogen atom, a C ₁ - ₄ alkyl group, a halogen atom or the radicals -OR ⁶ or -NR ⁷ R ^8, wherein R ⁶ represents a hydrogen atom, an optionally substituted by hydroxyl C ₁ -C ₆ alkyl group or a optionally substituted aryl or optionally substituted aralkyl groups in the aryl part, and

R ⁷ and R ^{8 are} hydrogen atoms, C ₁ -C ₆ -alkyl groups optionally substituted by hydroxyl groups or optionally

substituted aryl or optionally substituted aralkyl groups or together with the nitrogen atom to which they are attached represent a heterocyclic radical, and optionally their physiologically tolerable salts for the preparation of agents for acne, psoriasis and other dermatological diseases associated with pathological cornification and against iatrogenic or skin damage caused by UV light against eczema, warts, vitiligo, dry eyes and other corneopathies, also against precancerous and tumors as well

rheumatic and arthritic diseases.

2. Use of (all-E) -1- (4-carboxyphenyl) -4-methyl-6- (2,6,6-trimethyl-1-cyclohexen-1-yl) -1,3,5-hexatriene according to Claim 1.

3. Therapeutic remedy for acne, psoriasis and others with

dermatological diseases associated with pathological cornification as well as against iatrogenic or exposure to UV light

Damage to the skin, against eczema, warts, vitiligo, dry eyes and other corneopathies, furthermore against precancerous diseases and tumors as well as rheumatic and arthritic diseases, which contains an effective amount of a hexatriene derivative of the formula I as claimed in claim 1 in addition to conventional galenic aids.

4. Cosmetic ointment which contains 0.001 to 1% by weight of a hexatriene derivative of the formula I as claimed in claim 1 in addition to conventional auxiliaries.

5. Cosmetic for systemic use, which contains 0.1 to 50 mg of a hexatriene derivative of the formula I according to claim 1 per single dose.